Method for producing 2,4-dihydroxyquinoline derivatives

ABSTRACT

A method for producing a 2,4-dihydroxyquinoline derivative of the formula: ##STR1## wherein each of R 1 , R 2 , R 3  and R 4  is a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom, and its tautomer, which comprises cyclizing an aryl malonic acid amide ester derivative of the formula: ##STR2## wherein R 1 , R 2 , R 3  and R 4  are as defined above, and R 5  is a lower alkyl group, by means of polyphosphoric acid.

The present invention relates to a method for producing2,4-dihydroxyquinoline derivatives and their tautomers, which are usefulas intermediates for the preparation of medicines and agriculturalchemicals.

For the production of 2,4-dihydroxyquinoline derivatives, it is known toreact an aniline derivative with an excess amount of a malonate forhydrolysis, or to react an aniline derivative with malonic acid.(Michiaki Tominaga et al., Chem. Pharm. Bull., 29(8), 2161-2165 (1981),E. Zieglar and K. Gelfert, Monatsu. Chem., 90,822 (1959), J. L. Bose andR. C. Shah, J. Sci. Ind. Research (India) 19B, 176 (1960), and G. H.Patel and C. M. Mehta, J. Sci. Ind. Research, 19B, 436-438 (1960)).

However, such conventional methods have the following drawbacks. Namely,the method of using a malonate has drawbacks such that is involves anumber of process steps although the yield in each step is high, theisolation of intermediats in the respective steps is cumbersome, and thecyclization precursor which is precipitated with an acid from an aqueoussolution, contains a substantial amount of water in the crystals and istherefore required to be dried completely. On the other hand, the methodfor producing a 2,4-dihydroxyquinoline derivative in one step by usingmalonic acid in the absence of a solvent or in a carboxylic acid solventsuch as acetic acid or propionic acid, has drawbacks such that the yieldis low, a substantial amount of chlorine gas is produced as aby-product, and the operability of the process is poor although thenumber of process steps is small.

Under the circumstances, the present inventors have conducted extensivestudies to solve such problems of the conventional methods, by paying anattention to the conventional method of using a malonate, wherein theyield in each step is high, and as a result, have found it possible toobtain a 2,4-dihydroxyquinoline derivative in good yield with highselectivity in one step by subjecting the intermediate aryl malonic acidamide ester to a cyclization reaction by means of a certain specificpolyphosphoric acid without hydrolyzing it. The present invention hasbeen accomplished on the basis of this discovery.

Namely, it is an object of the present invention to provide a method forreadily producing a 2,4-dihydroxyquinoline derivative in good yield andwith high selectivity.

The present invention provides a method for producing a2,4-dihydroxyquinoline derivative of the formula: ##STR3## wherein eachof R¹ R², R³ and R⁴ is a hydrogen atom, a lower alkyl group, a loweralkoxy group or a halogen atom, and its tautomer, which comprisescyclizing an aryl malonic acid amide ester derivative of the formula:##STR4## wherein R¹, R², R³ and R⁴ are as defined above, and R⁵ is alower alkyl group, by means of polyphosphoric acid.

Now, the present invention will be described in detail with reference tothe preferred embodiments.

Each of R¹ to R⁴ in the formula I may be a hydrogen atom; an alkyl grouphaving from 1 to 4 carbon atoms such as a methyl group, an ethyl group,a propyl group or a butyl group; an alkoxy group having from 1 to 4carbon atoms such as a methoxy group, an ethoxy group, a propoxy groupor a butoxy group; or a halogen atom such as chlorine or bromine.

R⁵ is removed by the reaction of the present invention. Therefore, thereis no particular restriction as to R⁵ so long as it does not adverselyaffect the reaction of the invention. R⁵ is usually a lower alkyl groupsuch as a methyl group, an ethyl group, a propyl group or a butyl group.

Such an aryl malonic acid amide ester can be prepared by a conventionalmethod and has the above-mentioned substituents. Specifically, itincludes a methyl ester, an ethyl ester and a propyl ester of phenylmalonic acid amide, a methyl ester, an ethyl ester, a propyl ester andan isopropyl ester of (2,3-dimethylphenyl) malonic acid amide, a methylester, an ethyl ester and a propyl ester of chlorophenyl malonic acidamide, and a methyl ester of methoxyphenyl malonic acid amide.

Each of R¹ to R⁴ is not restricted to the above-mentioned carbon numberand may be an alkyl group or an alkoxy group having a higher number ofcarbon atoms so long as the reaction of the present invention is notadversely affected.

With respect to the polyphosphoric acid to be used in the presentinvention, it is generally known that a polyphosphoric acid will have adifferent polymerization degree (n) of a polyphosphoric acid representedby the following formula III by changing the molar ratio of 85%phosphoric acid and phosphorus pentoxide (P₂ O₅) (F. B. Popp, W. E.McEweu, Chem. Rev., 58,321 (1958)). ##STR5##

In the present invention, it is possible to use a polyphosphoric acidprepared in a molar ratio of P₂ O₅ /H₃ PO₄ within a range of from 0.2 to2.0. From the viewpoint of the reaction rate and selectivity, it isparticularly preferred to employ a polyphosphoric acid prepared in amolar ration of P₂ O₅ /H₃ PO₄ within a range of from 0.4 to 0.6.

The polyphosphoric acid is used usually in an amount of from 0.1 to 50ml, preferably from 0.2 to 20 ml, relative to 1.0 g of the aryl malonicacid amide ester derivative.

Since the polyphosphoric acid serves as a solvent, no other solvent maybe employed. However, a solvent which is inert to the reaction of thepresent invention may be employed as the case requires. For example, asolvent which is not completely missible with the polyphosphoric acid,such as a non-polar solvent such as toluene or xylene, may be employed.

The reaction temperature is usually from 50° to 200° C., preferably from100° to 150° C., since the lower the temperature, the higher theselectivity.

The 2,4-dihydroxyquinoline derivative obtained by the present inventionis represented by the formula II. However, the compound of the presentinvention can take the form of its tautomer represented by the followingformula II'. ##STR6##

Thus, the compound of the formula II' is also within the scope of thepresent invention.

Now, the present invention will be described in further detail withreference to Examples. However, it should be understood that the presentinvention is by no means restricted by such specific Examples.

In the Examples, the analytical condition for the liquid chromatography(LC) are as follows:

Column: Nucleosil-5-CN

Mobile phase: 0.05 mol KH₂ PO₄ /CH₃ CN=85 vol%/15 vol%

Temperature: 45° C.

Flow rate: 1.0 ml/min.

Detection method: UV-230 nm

EXAMPLE 1

50 g of P₂ O₅ was added to 50 ml of 85% H₃ PO₄ and the mixture wasstirred at 100° C. for two hours to obtain polyphosphoric acid. (Molarratio of P₂ O₅ /H₃ PO₄ : 0.48)

1 ml of the above polyphosphoric acid was added to 0.1 g of a methylester of (2,3-dimethylphenyl) malonic acid amide, and the mixture wasreacted at 130° C. for two hours. After completion of the reaction, thereaction solution was poured into water, and subjected to liquidchromatography analysis (LC analysis). The starting material i.e. thedimethyl ester of (2,3-dimethylphenyl) malonic acid amide was notobserved (conversion: 100%), and 65.1 mg (yield: 75%) of4-hydroxy-7,8-dimethyl-2-quinolone as the desired product, 0.1 mg(yield: 1%) of mono(2,3-dimethylphenyl) malonic acid amide as anintermediate and 7.7 mg (yield: 14%) of 2,3-xylidine as a by-productwere obtained. The results are shown in Table 1.

EXAMPLE 2

25 g of P₂ O₅ was added to 20 ml of 85% H₃ PO₄, and the mixture wasstirred at 100° C. for two hours to obtain polyphosphoric acid. (Molarratio of P₂ O₅ /H₃ PO₄ : 0.6)

1 ml of the above polyphosphoric acid was added to 0.1 g of a methylester of (2,3-dimethylphenyl) malonic acid amide, and the mixture wasreacted at 130° C. for two hours. After completion of the reaction, thereaction solution was poured into water and subjected to LC analysis.

The starting material i.e. the dimethyl ester of (2,3-dimethylphenyl)malonic acid amide was not observed (conversion: 100%), 58.8 mg (yield:67%) of 4-hydroxy-7,8-dimethyl-2-quinolone as the desired product, 7.1mg (yield: 7%) of mono(2,3-dimethylphenyl) malonic acid amide as anintermediate and 6.9 mg (yield: 12%) of 2,3-xylidine as a by-productwere obtained. The results are shown in Table 1.

EXAMPLE 3

61.2 g of P₂ O₅ was added to 39 ml of 85% H₃ PO₄, and the mixture wasstirred at 100° C. for two hours to obtain polyphosphoric acid. (Molarratio of P₂ O₅ /H₃ PO₄ : 0.76)

1 ml of the above polyphosphoric acid was added to 0.1 g of a methylester of (2,3-dimethylphenyl malonic acid amide, and the mixture wasstirred at 130° C. for two hours. After completion of the reaction, thereaction solution was poured into water and subjected to LC analysis.

The starting material i.e. the dimethyl ester of (2,3-dimethylphenyl)malonic acid amide was not observed (conversion: 100%), and 46.8 mg(yield: 54%) of 4-hydroxy-7,8-dimethyl-2-quinolone as the desiredproduct, 18.0 mg (yield: 19%) of mono(2,3-dimethylphenyl) malonic acidamide as an intermediate and 4.6 mg (yield: 8%) of 2,3-xylidine as aby-product were obtained. The results are shown in Table 1.

EXAMPLE 4

25 g of P₂ O₅ was added to 12 ml of 85% H₃ PO₄, and the mixture wasstirred at 100° C. for two hours to obtain polyphosphoric acid. (Molarratio of P₂ O₅ /H₃ PO₄ : 1.0)

1 ml of the above polyphosphoric acid was added to 0.1 g of a methylester of (2,3-dimethylphenyl) malonic acid amide, and the mixture wasreacted at 130° C. for two hours. After completion of the reaction, thereaction solution was poured into water and subjected to LC analysis.

The starting material i.e. the dimethyl ester of (2,3-dimethylphenyl)malonic acid amide was not observed (conversion: 100%, and 38.2 g(yield: 44%) of 4-hydroxy-7,8-dimethyl-2-quinolone as the desiredproduct, 21.8 mg (yield: 23%) of mono(2,3-dimethylphenyl) malonic acidamide as an intermediate and 1.7 mg (yield: 3%) of 2,3-xylidine as aby-product were obtained. The results are shown in Table 1.

EXAMPLE 5

1 ml of the polyphosphoric acid (molar ratio of P₂ O₅ /H₃ PO₄ : 0.48) asused in Example 1 was added to 0.1 g of an ethyl ester of(2,3-dimethylphenyl) malonic acid amide, and the mixture was reacted at130° C. for two hours. After completion of the reaction, the reactionsolution was poured into water and subjected to LC analysis. Thestarting material i.e. the ethyl ester of (2,3-dimethylphenyl) malonicacid amide was not observed (conversion: 100%), and 70.5 mg (yield: 86%)of 4-hydroxy-7,8-dimethyl-2-quinolone as the desired product, 3.3 mg(yield: 4%) of mono(2,3-dimethylphenyl) malonic acid amide as anintermediate and 5.8 mg (yield: 11%) of 2,3-xylidine as a by-productwere obtained. The results are shown in Table 1.

EXAMPLE 6

1 ml of the polyphosphoric acid (molar ratio of P₂ O₅ /H₃ PO₄ : 0.48) asused in Example 1 was added to 0.1 g of an isopropyl ester of(2,3-dimethylphenyl) malonic acid amide, and the mixture was reacted at130° C. for two hours. After completion of the reaction, the reactionsolution was poured into water, and subjected to LC analysis. Thestarting material i.e. the isopropyl ester of (2,3-dimethylphenyl)malonic acid amide was not observed (conversion: 100%), and 19.6 mg(yield: 26%) of 4-hydroxy-7,8-dimethyl-2-quinolone as the desiredproduct, 0.5 mg (yield: 0.6%) of mono(2,3-dimethylphenyl) malonic acidamide as an intermediate and 0.6 g (yield: 1%) of 2,3-xylidine as aby-product were obtained. The results are shown in Table 1.

EXAMPLE 7

5 ml of the polyphosphoric acid (molar ratio of P₂ O₅ /H₃ PO₄ : 0.48) asused in Example 1 was added to 0.1 g of a methyl ester of(2,3-dimethylphenyl) malonic acid amide and the mixture was reacted at130° C. for two hours. After completion of the reaction, the reactionsolution was poured into water and subjected to LC analysis.

The starting material i.e. the methyl ester of (2,3-dimethylphenyl)malonic acid amide was not observed (conversion: 100%), and 68.9 mg(yield: 79%) of 4-hydroxy-7,8-dimethyl-2-quinolone as the desiredproduct, 0.1 mg (yield: 0.1%) of mono(2,3-dimethylphenyl) malonic acidamide as an intermediate and 6.6 mg (yield: 12%) of 2,3-xylidine as aby-product were obtained. The results are shown in Table 1.

EXAMPLE 8

0.5 ml of the phosphoric acid (molar ratio of P₂ O₅ /H₃ PO₄ : 0.48) asused in Example 1 was added to 0.1 g of an ethyl ester of(2,3-dimethylphenyl) malonic acid amide, and the mixture was reacted at130° C. for two hours. After completion of the reaction, the reactionsolution was poured into water and subjected to LC analysis.

The starting material i.e. the ethyl ester of (2,3-dimethylphenyl)malonic acid amide was 5.1 mg (conversion: 95%), and 63.7 mg (yield:79%) of 4-hydroxy-7,8-dimethyl-2-quinolone as the desired product, 3.4mg (yield: 4%) of mono(2,3-dimethylphenyl) malonic acid amide as anintermediate and 3.3 mg (yield: 6%) of 2,3-xylidine as a by-product wereobtained. The results are shown in Table 1.

                                      TABLE 1                                     __________________________________________________________________________                                                     Yield of                                                                      mono-                                                                         (2,3-                                                     Conversion of                                                                         Yield of 2,4-                                                                             dimethyl-                                   Reaction conditions                                                                         aryl malonic                                                                          dihydroxy-                                                                           Yield of                                                                           phenyl)                      Aryl malonic acid     Molar ratio                                                                          acid amide                                                                            quinoline                                                                            2,3- malonic                      amide ester    Temp.                                                                             Time                                                                             of     ester   derivative                                                                           xylidine                                                                           acid amide                   derivative     (°C.)                                                                      (hr)                                                                             P.sub.2 O.sub.5 /H.sub.3 PO.sub.4                                                    (%)     (%)    (%)  (%)                          __________________________________________________________________________    Example 1                                                                           Methyl ether of                                                                        130 2  0.48   100     75     14   1                                  (2,3-dimethyl-                                                                phenyl) malonic                                                               acid amide                                                              Example 2                                                                           Methyl ether of                                                                        "   "  0.60   100     67     12   7                                  (2,3-dimethyl-                                                                phenyl) malonic                                                               acid amide                                                              Example 3                                                                           Methyl ether of                                                                        "   "  0.76   100     54     8    19                                 (2,3-dimethyl-                                                                phenyl) malonic                                                               acid amide                                                              Example 4                                                                           Methyl ether of                                                                        "   "  1.0    100     44     3    23                                 (2,3-dimethyl-                                                                phenyl) malonic                                                               acid amide                                                              Example 5                                                                           Ethyl ether of                                                                         "   "  0.48   100     86     11   4                                  (2,3-dimethyl-                                                                phenyl) malonic                                                               acid amide                                                              Example 6                                                                           Isopropyl ester                                                                        130 2  0.48   100     26     1    0.6                                of (2,3-dimethyl-                                                             phenyl) malonic                                                               acid amide                                                              Example 7                                                                           Methyl ester of                                                                        "   "  "      100     79     12   0.1                                (2,3-dimethyl-                                                                phenyl) malonic                                                               acid amide                                                              Example 8                                                                           Ethyl ester of                                                                         "   "  "      95      79     6    4                                  (2,3-dimethyl-                                                                phenyl) malonic                                                               acid amide                                                              __________________________________________________________________________

According to the present invention, the cyclization reaction can beconducted in good yield and with high selectivity in one step reaction,and the 2,4-dihydroxyquinoline derivative as the desired product canreadily be prepared. In particular, 7,8-dimethyl-2,4-dihydroxyquinolineproduced by the method of the present invention is particularly usefulas an intermediate for the preparation of a compound useful as atreating agent of allergic asthema (Japanese Unexamined PatentPublication No. 109000/1977).

REFERENCE EXAMPLE 1

10 g of 4-hydroxy-7,8-dimethyl-2-quinolone was added to 60 cc ofethylene dichloride, and 14 g of aluminum chloride was added theretounder stirring at room temperature. The reaction solution was firstslurried by the formation of a complex and then became a uniformsolution. Then, a solution of a mixture of 5.3 cc of acetyl chloride and16 cc of ethylene dichloride was dropwise added thereto at roomtemperature, and the acetylation reaction was conducted at 50° C. for 3hours. The reaction solution was cooled to room temperature, and 50 ccof water was carefully added for hydrolysis. Then, 5 cc of propionicacid was added thereto, and ethylene dichloride was distilled offtogether with water under heating, and the mixture was aged at 100° C.for 3 hours under stirring. The slurry was cooled at room temperatureand subjected to filtration. The obtained crystals were dried to obtain11.5 g of 3-acetyl-4-hydroxy-7,8-dimethyl-2-quinolone. Yield was 94%,and the purity was 98% (as analyzed by liquid chromatography). ##STR7##

REFERENCE EXAMPLE 2

4.54 g of 63% sodium hydride was added to 66 cc of toluene, and whilestirring the mixture at room temperature, 33 cc of isoamyl alcohol wasdropwise added thereto. The mixture was further stirred at 50° C. forone hour to obtain sodium isoamyl alcolate. Then, 10 g of3-acetyl-4-hydroxy-7,8-dimethyl-2-quinolone was added in its solid statethereto, and 20 g of diisoamyl oxalate was dropwise added thereto,whereupon the condensation reaction was conducted at 50° C. for 3 hours.The reaction solution was initially a slurry, but then changed into areddish brown uniform solution. The reaction solution was cooled to roomtemperature, and then acidified with the mixture of 7.38 g ofconcentrated sulfonic acid, 47 cc of isoamyl alcohol and 14 cc oftoluene. Then, the cyclization reaction was conducted at 80° C. for twohours while removing formed water. The reaction solution was initially ayellow slurry but turned into a substantially uniform solution at thecompletion of the reaction. Then, toluene was distilled off underreduced pressure at 40° C., and 130 cc of n-heptane was added. Themixture was subjected to precipitation at room temperature for one hour.The slurry thereby obtained was neutralized with an aqueous solution of0.5 N sodium bicarbonate. The crystals were collected by filtration andwashed twice with 50 cc of water and dried under reduced pressure toobtain 13.52 g ofisoamyl-5,6-dihydro-7,8-dimethyl-4,5-dioxo-4H-pyrano[3,2-C]quinolone-2-carboxylate(yield: 88% based on 3-acetyl-4-hydroxy-7,8-dimethyl-2-quinolone) with apurity of 99% (as measured by liquid chromatography).

I claim:
 1. A method for producing a 2,4-dihydroxyquinoline compound ofthe formula:wherein each of R¹, R², R³ and R⁴ is a hydrogen atom, alower alkyl group, a lower alkoxy group or a halogen atom, and itstautomer, which comprises cyclizing an aryl malonic acid amide estercompound of the formula: ##STR9## wherein R¹, R², R³ and R⁴ are asdefined above, and R⁵ is a lower alkyl group, by means of polyphosphoricacid at a temperature of from 50° C. to 200° C., wherein saidpolyphosphoric acid is prepared in a molar ratio of P₂ O₅ /H₃ PO₄ withina range of from 0.4 to 0.6.
 2. The method of claim 1, wherein saidcyclizing is carried out in a solvent which is selected from the groupconsisting of toluene and xylene.
 3. The method of claim 1, wherein saidtemperature is from 100° to 150° C.
 4. The method of claim 4, whereinsaid polyphosphoric acid is present in an amount of from 0.1 to 50 mlrelative to 1.0 g of said aryl malonic acid amide ester compound.